Endothelin-1 regulation of intercellular adhesion molecule-1 expression in normal and sclerodermal fibroblasts

J Cardiovasc Pharmacol. 1998;31 Suppl 1:S545-7. doi: 10.1097/00005344-199800001-00157.

Abstract

We investigated the potential modulation of cell surface intercellular adhesion molecule-1 (ICAM-1) expression and function by ET-1 in fibroblasts grown from skin biopsies of scleroderma (SSc) patients compared with healthy controls. Surface ICAM-1 expression was quantified by cell-bound ELISA and by FACS analysis. ICAM-1 function was investigated by measuring cell adhesion, and we studied ICAM-1 gene expression using RT-PCR. Fibroblast ET-1 binding sites were measured using 125I-labeled ET-1, and the modulation of ICAM-1 function by ET-1 was determined by measuring the binding of human U937 cells to fibroblasts in the presence of a mixed ETA/B receptor antagonist (bosentan) or a neutralizing anti-ICAM-1 antibody. ICAM-1 expression was significantly higher in SSc fibroblasts compared with normal controls. ET-1 increased ICAM-1 on both normal and SSc fibroblasts to comparable levels. RT-PCR demonstrated that ICAM-1 mRNA was upregulated by ET-1, and results from binding studies showed fibroblasts exposed to ET-1 supported more U937 cells than controls, a process that could be inhibited by bosentan and ICAM-1 neutralizing antibody. Autoradiography showed ET-1 receptors on both normal and SSc fibroblasts. Our findings indicate that SSc fibroblasts express intrinsically elevated levels of surface ICAM-1 and message. ET-1 can induce normal fibroblasts to express some SSc phenotypes and may function as a potent proinflammatory mediator, similar to cytokines, and therefore may also have immunoregulatory functions for immune cells infiltrating and binding to connective tissues.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoradiography
  • Cell Adhesion
  • Cells, Cultured
  • Endothelin-1 / drug effects
  • Endothelin-1 / physiology*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Intercellular Adhesion Molecule-1 / biosynthesis*
  • Intercellular Adhesion Molecule-1 / genetics
  • Polymerase Chain Reaction
  • Scleroderma, Systemic / metabolism*

Substances

  • Endothelin-1
  • Intercellular Adhesion Molecule-1